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Vitamin A supplementation for preventing morbidity and mortality in very-low-birth-weight infants

RHL Commentary by Bhutta ZA

1. EVIDENCE SUMMARY

The review was updated in 2007 and now includes eight trials and additional information provided by some of the authors of trials already included. The results of the meta-analysis remain the same and show a small but significant reduction in death or oxygen use at one month after birth (Relative risk [RR]: 0.93; 95% confidence interval [CI]: 0.88 0.99).

While the overall strategy for extraction of information and meta-analysis by the reviewers is sound, there are several limitations to the analysis that should be recognized. Given the close relationship of maternal vitamin A status and fetal lung development, maternal nutritional status should have been included as a variable. In particular, given that data from Black South African newborn VLBW infants are also included, it would also be important to look at maternal HIV positivity, which is an important correlate of maternal vitamin A status in developing countries, (1,2). Although most of the VLBW infants were premature, no information is provided on postnatal feeding. There were significant differences in overall vitamin A intake from parenteral feeds in the two studies from North America and it is likely that such differences in vitamin A intake may have influenced the outcome.

More importantly, as the reviewers themselves indicate, these studies span a long period of time which has witnessed dramatic changes in the management of VLBW infants, with increased use of antenatal and postnatal steroids, and almost universal surfactant administration. Surfactant therapy and postnatal steroids have also led to significant improvement in neonatal survival from respiratory distress syndrome (RDS) with reduced rates of chronic lung disease (CLD), and in any meta-analysis with studies from the pre-surfactant era, these confounding factors must be accounted for. The impact of postnatal steroids on increasing plasma vitamin A concentrations are important to take into account when correlating vitamin A dosage and plasma vitamin A concentrations with outcome.

Finally, given that infections account for a large proportion of deaths among hospitalized VLBW infants, (3) and that the objective of vitamin A supplementation programmes globally is to reduce childhood, (4) and neonatal mortality (5), from infectious diseases, it is surprising that infections do not figure as an important outcome in this systematic review. It is important to note that in the large multicentre trial of vitamin A supplementation in VLBW infants, (6), there was a trend towards lower rates of sepsis and necrotizing enterocolitis.

2. RELEVANCE TO UNDER-RESOURCED SETTINGS

2.1. Magnitude of the problem

In contrast to outcomes such as neonatal CLD and retinopathy of prematurity, for much of the developing world the importance of vitamin A in early infancy is with regards to its impact on survival through reduction in the risk of pneumonia and other respiratory infections. While these infections have not been shown to be affected significantly by vitamin A supplementation programmes in pre-schoolchildren (7), reduction in pneumonia-associated mortality, (8), the impact of neonatal vitamin A administration on immunity (9), and improved neurodevelopmental outcome, (10), is well recognized. Not withstanding the above, there have been significant improvements in neonatal care in many centres of the developing world with improved survival of high-risk VLBW infants. (11,12) The findings of this meta-analysis may thus be of relevance to clinical practice in neonatal referral centres in the developing world.

2.2. Applicability of the intervention

The findings of this meta-analysis may be of potential benefit to clinical practice in referral centres of the developing world. It may be appropriate for such centres to selectively provide vitamin A to high-risk VLBW infants. It must be pointed out, however, that even where resources permit specialized newborn care, the most important intervention in preventing morbidity and mortality in VLBW infants is breast milk feeding(13).

2.4. Implementation of the intervention

For multiple reasons cited above, the results of this Cochrane Review are not robust enough to justify implementation of vitamin A supplementation in much of the developing world. They could however, become part of an overall programme to improve vitamin A intake of mothers and infants.

There is a clear need to improve the provision of vitamin A to malnourished mothers and newborns in developing countries. However, the intramuscular mode of administration of vitamin A in most of the cited studies by Darlow and Graham would be problematic, because of the potential risk of secondary infections. Although there has been some concern about enteral absorption of vitamin A in VLBW infants, (14), others have reported satisfactory absorption of 25000 units vitamin A as a supplement (7), or from a formula providing 870 retinol equivalents/MJ (15). The findings of the Wardle trial (16), which used enteral vitamin A supplementation are in broad agreement with the results from trials using intramuscular vitamin A. Thus vitamin A supplementation programmes in early infancy, could be modified to provide vitamin A as well as other micronutrients to all lactating mothers and their VLBW infants at risk of problems.

2.5. Research

The potential of adverse effects of vitamin A administration to newborn infants merits a more robust evaluation than simple clinical "assessment" of a bulging fontanelle. Although the follow up data from a neonatal vitamin A supplementation programme in Nepal (10), are reassuring, there is a need for continued caution with regard to vitamin A supplementation in VLBW infants. There is a clear need now to define more robust measures of assessing vitamin A status such as whole body vitamin A measurement, than plasma concentrations alone.

References

• Semba RD, Miotti PG, Chiphangwi JD, Liomba G, Yang LP, Saah AJ, Dallabetta GA, Hoover DR. Infant mortality and maternal vitamin A deficiency during human immuodeficiency virus infection. Clinical infectious diseases 1995;21:966-972.
• Phuapradit W, Chaturachinda K, Taneepanichskul S, Sirivarasry J, Khupulsup K, Lerdvuthisopon N. Serum vitamin A and beta-carotene levels in pregnant women infected with human immunodeficiency virus-1. Obstetrics and gynecology 1996;87:564-567.
• Stoll BJ, Gordon T, Korones SB et al.. Early-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. Journal of pediatrics 1996;129:72-80.
• Beaton GH, Martorell R, Aronson KJ, Edmonston B, McCabe G, Ross AC, Harvey B. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. ACC/SCN Nutrition Policy Discussion Paper No. 13, pp1-120. World Health Organization, Geneva 1993 .
• Humphrey JH, Agoestina T, Lee W, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP, Sommer Al. Impact of neonatal vitamin A supplementation on infant morbidity and mortality. Journal of pediatrics 1996;128:489-496.
• Tyson E, Wright LL, Oh W et al. Vitamin A supplementation for extremely low birth-weight infants. New England journal of medicine 1999;340:1962-68
• The Vitamin A and Pneumonia Working Group. Potential interventions for the prevention of childhood pneumonia in developing countries: a meta-analysis of data from field trials to assess the impact of vitamin A supplementation on pneumonia morbidity and mortality. Bulletin of the World Health Organization 1995;73:609-619.
• Rahman MM, Mahalanabis D, Alvarez JO, Wahed MA, Islam MA, Habte D. Effect of early vitaminA supplementation on cell-mediated immunity in infants younger than 6 months. American journal of clinical nutrition 1997;65:144-148.
• Humphrey JH, Agoestina T, Juliana A, Septiana S, Widjaja H, Cerreto MC, Lee WSF, Ichord RN, Katz J, West KP. Neonatal vitamin A supplementation: effect on development and growth at 3 y of age. American journal of clinical nutrition 1998;68:109-117.
• Cooper PA, Sandler DL. Outcome of very low birth weight infants at 12 to 18 months of age in Soweto,South Africa.. Pediatrics 1997/YR;99VL:537-544.
• Bhutta ZA, Yusuf K. Survival and outcome of very low birth weight infants in a developing country: how feasible is early discharge. Royal College of Paediatrics and Child Health Annual Meeting, York, UK, April. London, Royal College of Paediatrics and Child Health (Programme and Abstracts G109) 1997 .
• Rush MG, Shenai JP, Parker RA, Chytill Fl. Intramuscular versus enteral vitamin A supplementation in very low birth weight neonates. The journal of pediatrics, 1994;125:458-462.
• Bhutta ZA. Spectrum of neonatal bacterial infections in developing countries: strategies for prevention. Seminars in neonatology 1999;4:159-171.
• Coutsoudis A, Adhikari M, Pillay K, Coovadia HM. Absorption of high-dose enteral vitamin A in low-birth-weight neonates. South African medical journal 1996;86:1337-1339.
• Koo WW, Krug-Wispe S, Succop P, Tsang RC, Neylan M. Effect of different vitamin A intakes on very-low-birth-weight infants. American journal of clinical nutrition, 1995;62:1216-1220.
• Wardle SP, Hughes A, Chen S, Shaw NJ. Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease. Archives of diseases in childhood. Fetal and neonatal edition 2001;84:F9-F13.

This document should be cited as: Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in very-low-birth-weight infants : RHL commentary (last revised: 26 March 2008). The WHO Reproductive Health Library; Geneva: World Health Organization.

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